Growth factors in general, and brain-derived neurotrophic factor (BDNF) in particular, play critical roles in the nervous system to regulate neuronal development and survival, axonal outgrowth, synaptogenesis, and synaptic plasticity. BDNF signaling modifies depressive behavior, and a large number of studies demonstrate additional roles for BDNF/TrkB pathways in contextual fear conditioning and spatial memory, as well as in the regulation of synaptic plasticity and the induction of long term potentiation (LTP). These functions likely depend on genes or gene products that BDNF regulates at the transcriptional, translational or post-translational levels, several via activation of the transcription factor CREB, a critical molecular regulator of memory in a number of different species. However, few candidate genes downstream of neurotrophins and CREB that contribute to memory formation have been identified. Recent studies suggest that VGF, a neuronal secreted protein and peptide precursor that is rapidly induced by the neurotrophins BDNF, NGF and NT3, plays a role in memory formation. VGF-derived peptides are known to regulate synaptic plasticity, reproductive behavior and energy balance. Recent human genetic SNP mapping has identified a VGF polymorphism that results in premature VGF termination after amino acid 524, eliminating several bioactive VGF peptides and an alpha-helical region required for regulated secretion. Preliminary data included in this proposal show that VGF C-terminal peptides have anti-depressant efficacy and also regulate hippocampal neuronal electrical excitability and synaptic plasticity in hippocampal slices, consistent with impaired performance of VGF knockout mice in spatial memory tasks (e.g. Morris water maze) and contextual fear conditioning. In Aim 1 of the R21 phase, we will develop two mouse models that knock human VGF alleles into the mouse Vgf locus, encoding either full length human VGF (amino acids 1-615) or SNP-truncated VGF (amino acids 1-524). In Aim 1 of the R33 phase, we will test expression and function of human VGF in these mouse models, determining whether carriers of this polymorphism could be predisposed to depression and impaired cognition, much as those with aberrant BDNF expression and/or signaling are at risk for memory and behavioral disorders. Performance of VGF knock-in mice will be examined in spatial and contextual fear memory tasks, and in depression and anxiety testing. Overall, the proposed experiments will investigate the roles that VGF, VGF-derived peptides, and a specific polymorphism in the human VGF gene, play in the regulation of hippocampal synaptic plasticity, depression, and hippocampal-dependent memory. Relevance to Public Health: Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression. to Public Health: Neurotrophic growth factors play critical roles in the nervous system to regulate brain development and function, but few candidate genes have been identified that are induced by neurotrophins and contribute to memory formation and behavior. Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression.